公开(公告)号：US06222013B1

公开(公告)日：2001-04-24

申请号：US09425023

申请日：1999-10-25

申请人： Wilhelmus H. J. Boesten ,  Peter J. L. M. Quaedflieg

发明人： Wilhelmus H. J. Boesten ,  Peter J. L. M. Quaedflieg

IPC分类号： C07K100

CPC分类号： C07K5/06026 ,  C07C227/18 ,  C07C305/06 ,  C07D207/16 ,  C07K1/107 ,  C07K5/0613

摘要： A process is disclosed for the esterification of an amino acid or peptide in which the amino acid or peptide is converted into the corresponding ester in the presence of a hydrosulphate have the general formula ROSO3H, where R represents an alkyl group, with the hydrosulphate being prepared, in the presence of the amino acid or peptide, from chlorosulphonic acid and an alcohol having the general formula ROH, where R has the same meaning as above. The chlorosulphonic acid to amino acid or peptide molar ratio preferably is between 0.8 and 2.0, in particular between 1.0 and 1.3. A primary alcohol, in particular methanol, is preferably used as alcohol. The amino acid used may be for example an &agr;-amino acid chosen from the group comprising p-hydroxyphenylglycine, phenylglycine, phenylalanine, tyrosine, proline and valine; L-alanyl-L-proline or an ester of L-aspartyl-L-phenylalanine, for example, may be used as peptide.

摘要翻译： 公开了一种氨基酸或肽的酯化方法，其中氨基酸或肽在硫酸氢盐存在下转化成相应的酯，具有通式ROSO 3 H，其中R表示烷基，其中制备硫酸氢盐 在氨基酸或肽的存在下，由氯磺酸和具有通式ROH的醇，其中R具有与上述相同的含义。 氯磺酸与氨基酸或肽的摩尔比优选在0.8和2.0之间，特别是在1.0和1.3之间。 优选使用伯醇，特别是甲醇作为醇。 所使用的氨基酸可以是例如选自对羟基苯基甘氨酸，苯基甘氨酸，苯丙氨酸，酪氨酸，脯氨酸和缬氨酸的α-氨基酸; 例如，L-丙氨酰-L-脯氨酸或L-天冬氨酰基-L-苯丙氨酸的酯可用作肽。

公开(公告)号：US5276190A

公开(公告)日：1994-01-04

申请号：US950713

申请日：1992-09-25

申请人： Wilhelmus H. J. Boesten ,  Harold M. Moody ,  Quirinus B. Broxterman

发明人： Wilhelmus H. J. Boesten ,  Harold M. Moody ,  Quirinus B. Broxterman

IPC分类号： C07C213/00 ,  C07C215/08 ,  C07C215/28 ,  C07C319/20 ,  C07C323/24 ,  C07C323/29 ,  C07C209/68

CPC分类号： C07C319/20 ,  C07C213/00

摘要： The invention relates to a method for the preparation of an .alpha.,.alpha.-disubstituted .alpha.-amino alcohol from the corresponding amide with the aid of sodium in the presence of an alcohol as solvent. The conversion of amino acid amide to amino alcohol proceeds virtually quantitatively. Moreover, the reduction of the amino acid amide to the corresponding amino alcohol proceeds with retention of optical activity.

摘要翻译： 本发明涉及在醇作为溶剂的存在下，借助于钠从相应的酰胺制备（α），（α） - 二取代（α） - 氨基醇的方法。 氨基酸酰胺向氨基醇的转化实际上是定量的。 此外，将氨基酸酰胺还原成相应的氨基醇进行保留光学活性。

公开(公告)号：US07029885B2

公开(公告)日：2006-04-18

申请号：US09457765

申请日：1999-12-10

申请人： Harold M. Moody ,  Wilhelmus H. J. Boesten

发明人： Harold M. Moody ,  Wilhelmus H. J. Boesten

IPC分类号： C12N9/00

CPC分类号： C12P37/04

摘要： Ampicillin is produced in a batch process by enzymatic acylation of 6-aminopenicillanic acid (6-APA) with the aid of phenylglycine derivative such as D-phenylglycine amide. High conversions of phenylglycine derivative may be achieved by having the total concentration in the reaction mixture of 6-APA and ampicillin greater than 250 mM and the molar ration of total quantity of phenylglycine derivative to total quantity of 6-APA less than 2.5. Higher yields of ampicillin may be achieved when the amount of dissolved 6-APA is kept low, e.g. below 300 mM.

摘要翻译： 通过6-苯基甘氨酸衍生物如D-苯基甘氨酸酰胺的酶促酰基化6-氨基青霉烷酸（6-APA），分批生产氨苄青霉素。 苯基甘氨酸衍生物的高转化率可以通过使6-APA和氨苄青霉素的反应混合物中的总浓度大于250mM，苯基甘氨酸衍生物的总量与6-APA总量的摩尔比小于2.5来实现。 当溶解的6-APA的量保持较低时，可以获得较高的氨苄青霉素产量。 低于300mM。

公开(公告)号：US5859241A

公开(公告)日：1999-01-12

申请号：US821519

申请日：1997-03-21

申请人： Marcus J. M. Plaum ,  Wilhelmus H. J. Boesten

发明人： Marcus J. M. Plaum ,  Wilhelmus H. J. Boesten

IPC分类号： C07D281/10

CPC分类号： C07D281/10

摘要： Process for the preparation of a 1,5-benzothiazepine derivative, or a salt thereof, of formula 1 ##STR1## where R1 represents H, an alkyl group or an alkoxy group and R.sub.2 represents H or a halogen, in which process a propanoic acid derivative of formula 2 ##STR2## where R.sub.1 and R.sub.2 are as defined above and R.sub.3 represents H or an alkyl group is subjected to an intramolecular cyclisation reaction in a non-halogenated solvent in the presence of a carboxylic acid. Preferably, R.sub.2 is H and R.sub.1 is OCH.sub.3. Trichloroacetic acid is preferably used as .alpha.-chlorinated acid. The benzothiazepine obtained on cyclisation can be subjected to an alkylation reaction and/or an acylation reaction to obtain known pharmaceutical products, in particular diltiazem.

摘要翻译： 制备式1的1,5-苯并硫氮杂衍生物或其盐的方法，其中R 1表示H，烷基或烷氧基，R 2表示H或卤素，其中丙酸 式2的酸衍生物其中R 1和R 2如上所定义，R 3表示H或烷基在羧酸存在下在非卤化溶剂中进行分子内环化反应。 R2优选为H，R1为OCH3。 三氯乙酸优选用作α-氯代酸。 通过环化获得的苯并硫氮杂化物可进行烷基化反应和/或酰化反应，以获得已知的药物产品，特别是地尔硫卓。

公开(公告)号：US5336805A

公开(公告)日：1994-08-09

申请号：US928317

申请日：1992-08-12

申请人： Wilhelmus H. J. Boesten ,  Nicolaas A. de Heij

发明人： Wilhelmus H. J. Boesten ,  Nicolaas A. de Heij

IPC分类号： C07C227/10 ,  C07C227/18 ,  C07C229/08 ,  C07C229/36 ,  C07C231/14 ,  C07C229/00

CPC分类号： C07C231/14 ,  C07C227/10

摘要： Process for preparing an a-amino acid having the general formula (1) of ##STR1## where R represents an aryl group or a substituted aryl, cycloalkyl or alkyl group, in which process glyoxylic acid, or a precursor or derivative thereof, is contacted in the presence of sulphamic acid with an unsaturated compound chosen from the group of aromatics, cycloalkenes and alkenes. By applying the process higher efficiencies are obtained.The acid obtained as reaction product can be esterified and amidated without prior isolation.

摘要翻译： 制备具有通式（1）的化合物（1）的α-氨基酸的方法，其中R表示芳基或取代的芳基，环烷基或烷基，其中乙醛酸或其前体或衍生物 在氨基磺酸存在下与选自芳族化合物，环烯烃和烯烃的不饱和化合物接触。 通过应用该方法，可获得更高的效率。 作为反应产物获得的酸可以在没有预先分离的情况下酯化和酰胺化。

公开(公告)号：US4847412A

公开(公告)日：1989-07-11

申请号：US850157

申请日：1986-04-10

申请人： Wilhelmus H. J. Boesten ,  Hans E. Schoemaker ,  Bernardus H. N. Dassen

发明人： Wilhelmus H. J. Boesten ,  Hans E. Schoemaker ,  Bernardus H. N. Dassen

IPC分类号： C07B55/00 ,  C07B31/00 ,  C07C67/00 ,  C07C231/00 ,  C07C231/12 ,  C07C231/16 ,  C07C237/06 ,  C07C241/00 ,  C07C251/02 ,  C12P13/04 ,  C12P13/08 ,  C12P41/00

CPC分类号： C12P13/04 ,  C12P13/08 ,  C12P41/007

摘要： The invention relates to a process for racemizing an optically active N-benzylidene amino-acid amide, characterized in that a solution of the N-benzylidene amino-acid amide is mixed in a water-miscible organic solvent with at least 0.05 mole strong base per liter solution.The invention further relates to a process for preparing an L-amino acid by enzymatic separation of the corresponding DL-amino-acid amide with an enzyme preparation from Pseudomonas putida, in which process also unconverted D-amino-acid amide is left behind in solution, characterized in that benzaldehyde is added to the solution, during which addition a precipitate of D-N-benzylidene amino-acid amide is being formed, this precipitate is subsequently, after being separated off, dissolved in an acetone-water mixture, 0.08-0.15 mole KOH/liter solution is subsequently added, the resulting solution is stirred for 1-20 hours at 20.degree.-60.degree. C., sulphuric acid is then added until the pH of the solution is 5 and the resulting sulphuric acid salt of the DL-amino-acid amide is finally, after isolation at pH 8-10, converted into the DL-amino-acid amide and this DL-amino-acid amide is used again.

摘要翻译： 本发明涉及一种使光学活性的N-亚苄基氨基酸酰胺外消旋化的方法，其特征在于将N-亚苄基氨基酸酰胺的溶液与水混溶的有机溶剂混合至少0.05摩尔强碱 升解决方案。 本发明还涉及通过用恶臭假单胞菌（Pseudomonas putida）的酶制剂酶分离相应的DL-氨基酸酰胺来制备L-氨基酸的方法，其中将未转化的D-氨基酸酰胺留在溶液中 其特征在于向溶液中加入苯甲醛，在此期间加入了DN-亚苄基氨基酸酰胺的沉淀物，然后将该沉淀物分离后溶解在丙酮 - 水混合物中，0.08-0.15摩尔 随后加入KOH /升溶液，所得溶液在20-60℃下搅拌1-20小时，然后加入硫酸直到溶液的pH为5，得到的DL- 氨基酸酰胺最后在pH8-10分离后，转化成DL-氨基酸酰胺，再次使用该DL-氨基酸酰胺。

公开(公告)号：US4831181A

公开(公告)日：1989-05-16

申请号：US188418

申请日：1988-04-29

申请人： Wilhelmus H. J. Boesten ,  Bernardus H. N. Dassen

发明人： Wilhelmus H. J. Boesten ,  Bernardus H. N. Dassen

IPC分类号： C07K1/06 ,  C07K5/075

CPC分类号： C07K5/0613

摘要： The invention relates to a process for the preparation of aspartylphenylalanine methyl ester from N-formylaspartylalanine methyl ester by treatment with an acid, characterized in that N-formylaspartylalanine methyl ester is treated at 30.degree.-60.degree. C. with at least 0.5 molar equivalent oxalic acid per mole of N-formylaspartylphenylalanine methyl ester in a solvent mixture in which N-formylaspartylphenylalanine methyl ester dissolves well and in which the oxalic acid salt of aspartylphenylalanine methyl ester is poorly soluble, after which the oxalic acid salt of aspartylphenylalanine methyl ester is removed by filtration, dissolved in water subsequently neutralized with the aid of an inorganic base with formation of free aspartylphenylalanine methyl ester.

公开(公告)号：US4094904A

公开(公告)日：1978-06-13

申请号：US748398

申请日：1976-12-08

申请人： Wilhelmus H. J. Boesten

发明人： Wilhelmus H. J. Boesten

IPC分类号： C07C231/00 ,  C07B55/00 ,  C07C67/00 ,  C07C231/12 ,  C07C231/16 ,  C07C237/20 ,  C07C103/28

CPC分类号： C07B55/00

摘要： The invention is directed to a process for the racemization of optically active phenyl glycine amide with or without a substituted phenyl group by heating the opticaly active phenyl glycine amide in a solvent in the presence of a ketone and of an acid having a dissociation constant below 1.8 .times. 10.sup.-4.BACKGROUND OF THE INVENTIONThe resolution of a mixture of D- and L-phenyl glycine amide by means of an optically active acid is described in my co-pending U.S. patent applications Ser. No. 623,928, filed Oct. 20, 1975, and now U.S. Pat. No. 4,036,852 and Ser. No. 733,851, filed Oct. 19, 1976. An improved process for the resolution of a mixture of D- and L-phenyl glycine amide by means of an optically active acid is described in my co-pending U.S. patent application Ser. No. 748,399 filed concurrently herewith. The entire specification and claims of each of these three patent applications is incorporated by reference in the present specification.The invention relates to a process of racemizing an optically active phenyl glycine amide with or without a substituted phenyl group. The phenyl group may be substituted by a substituent such as a hydroxy, halogen, nitro, or amino group. These substituted optically active phenyl glycine amides can be prepared from the corresponding amino acid by esterification followed by aminolysis of the ester with ammonia as described in the Journal of the American Chemical Soc. vol. 71 (1949) page 78, 79.If desired, the racemized amide can be hydrolyzed to yield the corresponding amino acid again. Phenyl glycine amide can be hydrolyzed in a simple manner to form phenyl glycine, for example, by treatment with sulfuric acid, as described in the Journal of the Chemical Society, pages 393-397 (1966).In the preparation of an optically active phenyl glycine amide from a mixture of D- and L-phenyl glycine amide, both antipodes of the racemate are produced. If unequal amounts of the antipodes are desired, the undesired antipode can be racemized and the resulting racemate subjected to further resolution. As used in the present specification, "a mixture of L- and D-phenyl glycine amide" means either a racemate of phenyl glycine amide, or mixtures of the racemate with either L-phenyl glycine amide or D-phenyl glycine amide.The optically active phenyl glycines which can be easily obtained from the resolved optically active phenyl glycine amides are valuable compounds. For example, D-phenyl glycine is employed as a starting material for the preparation of .alpha.-amino benzyl penicillin. L-phenyl glycine provides a starting material for the sweetening agent L-asparagin-L-phenyl glycine alkyl ester.SUMMARY OF THE INVENTIONAccording to the invention, a process has been discovered comprising racemizing an optically active phenyl glycine amide, the phenyl group of which may be substituted, in an accelerated manner. It has been found that the racemization of a optically active phenyl glycine amide can be desirably conducted by heating the optically active phenyl glycine amide to be racemized in a solvent in the presence of a ketone and of an acid having a dissociation constant below 1.8 .times. 10.sup.-4. As used in the present application, it is to be understood that "an optically active phenyl glycine amide" includes both unsubstituted optically active phenyl glycine amide and optically active phenyl glycine amide in which the phenyl group is substituted with, for example, a hydroxy, halogen, nitro or amino group.It is therefore an object of the present invention to racemize an optically active phenyl glycine amide in an accelerated manner.Surprising, it has been found that the object of the present invention can be realized by racemizing an optically active phenyl glycine amide in the presence of a ketone and of an acid having a dissociation constant below 1.8 .times. 10.sup.-4.DETAILED DESCRIPTION OF THE INVENTIONThe invention is directed to a process of racemizing an optically active phenyl glycine amide, the phenyl group of which may be substituted, in a solvent in the presence of a ketone and of an acid having a dissociation constant below 1.8 .times. 10.sup.-4.Suitable acids are, for example, formic acid and acetic acid. In addition, use may be made of optically active acids e.g. optically active pyrrolidone-5-carboxylic acid and optically active N-acetyl phenyl glycine. These optically active acids are also suitable for the optical resolution of mixtures of D- and L-phenyl glycine amide, as described in my co-pending applications incorporated herein by reference.In the process of the present invention, preferably a quantity of acid is used which is equivalent to the quantity of phenyl glycine amide. An amount less than an equivalent amount, e.g. half the equivalent amount, of acid can also be used, but in that case undesirable side reactions may occur. A quantity of acid which is in excess of the equivalent of the phenyl glycine amide present may also be used, although there is no particular advantage in using excess acid.The racemizing process of the present invention is preferably effected at a temperature between about 35.degree. and about 150.degree. C. It is preferred to effect the racemizing process of the present invention at a temperature between about 50.degree. and about 100.degree. C.The ketone used in the racemizing process of the present invention may be selected from the group consisting of acetone, methyl ethyl ketone, pentanone, cyclohexanone, and mixtures thereof. It is believed that other ketones will also be operative in the process of the present invention.The amount of ketone used in the process of the present invention may be varied within wide limits. It has been found that a small quantity of ketone, for example 0.1 mole of ketone per mole of phenyl glycine amide is effective in the process of the present invention. Of course, larger amounts of ketone may also be used. If the amount of ketone used is sufficiently large, the ketone can also serve as a solvent for the racemizing mixture. However, it is also contemplated in the process of the present invention that other solvents may be used. For example, water, an alcohol, benzene, toluene, chloroform, and ethyl acetate may also be used as solvents.The process of the present invention will be further illustrated by the following examples, which are intended to be illustrative only and are meant to include all techniques equivalent thereto.EXAMPLESEXAMPLE IIn a flask equipped with a stirrer and a reflux cooler a solution of 1.5 g (0.01 gmole) L-phenyl glycine amide and 0.6 ml (0.01 gmole) acetic acid in 20 ml water and 80 ml acetone is boiled for 24 hours (58.degree. C), with stirring and reflux.After cooling to 20.degree. C, the rotation of this solution is determined. It is[.alpha.].sub.D.sup. 20 = 0.3.degree.The rotation of the original solution is:[.alpha.].sub.D.sup. 20 = 5.1.degree..Comparison of these rotation values shows (50 - 50 .times. 0,3/5,1) .times. 2 = 94% of the L-phenyl glycine amide to have been racemized.EXAMPLE IIIn a flask equipped with a stirrer and a reflux cooler a solution of 1.5 g (0.01 gmole) L-phenyl glycine amide, 0.4 ml (0.011 gmole) formic acid in 50 ml methyl ethyl ketone and 10 ml water is boiled with reflux for 20 hours (80.degree. C).After cooling to 20.degree. C, the rotation of this solution is[.alpha.].sub.D.sup. 20 = +0.9.degree..the rotation of the original solution is[.alpha.].sub.D.sup. 20 = +7.7.degree..comparison of the rotation values shows 88% of the L-phenyl glycine amide to have been racemized.EXAMPLE IIIIn a flask equipped with a stirrer and a reflux cooler 1.5 g (0.01 gmole) L-phenyl glycine amide and 0.6 ml (0.01 gmole) acetic acid in a mixture of 50 ml methanol and 0.45 ml (0.005 gmole) methyl ethyl ketone is boiled with reflux for 6 hours at 60.degree. C.After cooling to 20.degree. C the rotation of the resulting solution is measured. It is[.alpha.].sub.D.sup. 20 = 5.05.degree.the rotation of the original solution is[.alpha.].sub.D.sup. 20 = 8.90.degree.comparison of the rotation values shows 44% of the L-phenyl glycine amide to have been racemized.EXAMPLE FOR COMPARISONExample III is repeated, this time without addition of methyl ethyl ketone.After 6 hours' boiling, the rotation of the solution is[.alpha.].sub.D.sup. 20 = 8.40.degree..comparison of the rotation values shows only 6% of the L-phenyl glycine amide to have been racemized.EXAMPLE IVIn a flask equipped with a stirrer and a reflux cooler 4.5 g L-phenyl glycine amide and 3.9 g D-2-pyrrolidone-5-carboxylic acid in 200 ml methanol and 10 ml acetone is heated at boiling temperature for 25 hours whilst being stirred.After cooling to 20.degree. C, 3 ml concentrated hydrochloric acid (35%-wt.) is added. Next, the reaction mixture is concentrated in vacuo (12 mm Hg) at 30.degree. C to a volume of 40 ml. The DL-phenyl glycine amide.HCl formed in this way is recovered on a filter and washed on this filter with 5 ml[.alpha.].sub.D.sup. 20 = +0.4.degree. (c = 0.8; water)In Beilstein 14, III, p. 1189. the specific rotation of L-phenyl glycine amide. HC1 is given as[.alpha.].sub.D.sup. 20 = +100.8.degree. (c = 0.8; water).Comparison of the rotation values shows 99,5% of the L-phenylglycine amide to have been racemized.Thus it is apparent that there has been provided in accordance with the invention, a process for the racemization of optically active phenyl glycine amide that fully satisfies the objects, aims, and advantages set forth above. While the invention has been described in conjunction with specific embodiments thereof, it is apparent that many alternatives, modifications, and variations will be evident to those skilled in the art in light of the foregoing description. Accordingly, it is intended to embrace all such alternatives, modifications, and variations as fall within the spirit and broad scope of the following claims. methanol. After drying, the resulting salt weighs 4.4 g. The specific rotation of this salt is

摘要翻译： 本发明涉及一种通过在酮和一种解离常数低于1.8的酸的存在下在溶剂中加热光学活性苯基甘氨酸酰胺来使具有或不具有取代的苯基的光学活性苯基甘氨酸酰胺外消旋化的方法 x 10-4。

公开(公告)号：US5916762A

公开(公告)日：1999-06-29

申请号：US940984

申请日：1997-09-30

申请人： Wilhelmus H. J. Boesten ,  Harold M. Moody ,  Eric C. Roos

发明人： Wilhelmus H. J. Boesten ,  Harold M. Moody ,  Eric C. Roos

IPC分类号： C07D499/00 ,  C12P37/04 ,  C07D499/18 ,  C12P37/00

CPC分类号： C07D499/00 ,  C12P37/04

摘要： Process for the recovery of ampicillin from a mixture containing ampicillin and 6-aminopenicillic acid (6-APA), in which a mixture of ampicillin and 6-APA, with a pH higher than 7, which apart from any solid ampicillin being present is homogeneous at a pH between 7 and 8.5, is subjected to a pH lowering till a pH lower than 8.2 is reached, and the solid substance present is recovered. The process is in particular suitable to be applied to the reaction mixture which is obtained after the enzymatic acylation reaction of 6-APA with a phenylglycidine derivative as acylation agent. Pure ampicillin can thus be recovered in a simple way.

摘要翻译： 从含有氨苄青霉素和6-氨基青蒿酸（6-APA）的混合物中回收氨苄青霉素的方法，其中氨苄西林和6-APA的混合物，pH高于7，除了存在任何固体氨苄青霉素之外 在pH7〜8.5之间，进行pH降低，直至达到低于8.2的pH值，并回收存在的固体物质。 该方法特别适用于6-APA与苯基甘氨啶衍生物作酰化剂的酰化反应后获得的反应混合物。 因此，可以简单的方式回收纯氨苄青霉素。

公开(公告)号：US5874571A

公开(公告)日：1999-02-23

申请号：US903879

申请日：1997-07-31

申请人： Wilhelmus H. J. Boesten ,  Eric C. Roos ,  Wilhelmus J. J. van den Tweel

发明人： Wilhelmus H. J. Boesten ,  Eric C. Roos ,  Wilhelmus J. J. van den Tweel

IPC分类号： C07D501/00 ,  C07D501/12 ,  C07D501/22 ,  C12P35/00 ,  C12P35/04 ,  C12P37/04 ,  C07D501/06

CPC分类号： C12P35/00 ,  C07D501/00

摘要： The disclosed process is for the recovery of cephalexin from a mixture containing cephalexin and 7-aminodesacetoxy cephalosporanic acid (7-ADCA), wherein a mixture of cephalexin and 7-ADCA, with a pH higher than 7, which apart from any solid cephalexin being present is homogeneous at a pH between 7 and 8.5, is subjected to a pH modification until a pH lower than 7.8 is reached, and the solid substance is recovered. The disclosed process is particularly suited for application to a reaction mixture obtained after the enzymatic acylation reaction of 7-ADCA with a phenylglycine derivative as an acylation agent. Pure cephalexin can thus be recovered in a simple manner.

摘要翻译： 所公开的方法是从含有头孢氨苄和7-氨基二乙酰氧基头孢菌酸（7-ADCA）的混合物中回收头孢氨苄，其中除了任何固体头孢氨苄之外，pH高于7的头孢氨苄和7-ADCA的混合物 在pH7-7.5之间存在是均相的，经过pH调节，直到达到低于7.8的pH，并回收固体物质。 所公开的方法特别适用于7-ADCA与作为酰化剂的苯基甘氨酸衍生物进行酶酰化反应后得到的反应混合物。 因此可以简单的方式回收纯头孢氨苄。